This invention relates to novel compositions of matter and articles of manufacture which are useful for generating microbubbles in a liquid, for example in a liquid filling a vessel or chamber of the human body of a vessel or chamber of an industrial process, to methods of producing such microbubbles and to methods of using the microbubbles thus generated, including the enhancement of ultrasonic images of such liquid filled vessels or chambers containing the microbubbles.
It is known that contrast in ultrasonic images is enhanced by the presence of microbubbles in a liquid, e.g., the blood stream of a test subject. The prior art describes forming such microbubbles both externally of the test subject and then injecting the preformed microbubbles into the subject's blood stream and internally within the blood stream.
For example, microbubbles have been formed by simply vigorously agitating a liquid solution, such as normal saline solution, a dye solution, or a temporarily withdrawn aliquot of blood, prior to its injection into the blood stream. This can lead to significant ultrasonic image contrast enhancement, but these bubbles are generally of non-uniform size, often as large as 2000 microns in diameter which are potentially hazardous as gas emboli. Also, neither the size nor the concentration of the microbubbles can be quantitatively controlled for optimum contrast, thus limiting their usefulness. A method for obtaining microbubbles of a defined size by filtering bubbles produced by applying direct current potential across a silver plate is described in U.S. Pat. No. 3,640,271.
In the method of U.S. Pat. No. 4,276,885, very precise size microbubbles are formed with a coalescence resistant membrane, particularly gelatin, and then the precision microbubbles are injected into the blood stream. This procedure leads to significant image enhancement compared to an aerted saline solution. However, storage of the thus-produced microbubbles requires refrigeration or other techniques which will preserve the microbubbles.
In the procedure of U.S. Pat. No. 4,265,251, a solid microbubble precursor, particularly a saccharide composition having microbubbles of a gas, generally a pressurized gas, entrapped therein, is added to the blood stream. As the saccharide dissolves in the blood stream, the individual microbubbles are released into the blood stream. The thusgenerated microbubbles can be used to obtain an enhanced ultrasonic echographic image of a liquid containing the microbubbles. When the pressure in the cavities is different from the pressure in the blood stream, ultrasonic signals are produced on formation of the microbubbles, which can be used to measure local blood pressure. Although these microbubble precursors do not require the special storage treatment required for the precursors of U.S. Pat. No. 4,276,885, the number of microbubbles per unit volume of precursor which can be produced is inherently limited because of technological considerations.
While some of the prior art microbubbles, particularly the gelatin microbubbles and the microbubbles formed from the solid precursor, can be made relatively small, e.g., 10 microns mean size or even less, it is relatively more difficult and time consuming to make them in such a size range and requires the use of specialized equipment and carefully controlled parameters. This increases their cost and the very small gelatin microbubbles present storage difficulties because of their relatively short lifetime. Moreover, the number of microbubbles which can be generated in a liquid by microbubble-containing precursors is inherently limited to the number of microbubbles present in the precursor. Because the volume of precursor which can be added to a liquid is sometimes limited, e.g., in blood for physiological reasons, and both the number of microbubbles per unit volume of precursor which can be formed therein and the average size thereof are limited by technological factors, the echogenic opacification of liquids which can be achieved by such microbubble-containing precurors is less than optimum.
It would be desirable if a solid microbubble precursor could produce microbubbles in a liquid and especially in blood having a very small average diameter, e.g., about 10 microns, or less, in amounts greater than can feasibly be produced in a gel or solid microbubble-containing precursor.
It is an object of this invention to provide novel solid microbubble precursors which have the aforesaid microbubble producing capability. It is another object to provide solid microbubble precursors which are cheaper to produce than the solid precursors of U.S. Pat. No. 4,265,251. Still another object is to provide novel compositions of matter and articles of manufacture comprising such solid microbubble precursors.